Assessment of Endoscopy-Based Scoring Systems for Prognostication in Ulcerative Colitis: A Comparative Analysis.

BACKGROUND AND OBJECTIVE: Endoscopy-based scoring systems, including Mayo Endoscopic Score (MES), Modified Mayo Endoscopic Score (MMES), and Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) Score, have been introduced to evaluate UC prognosis. This study aims to compare their predictive capacity for clinical outcomes in UC patients. METHODS: Consecutive UC patients from a tertiary hospital were included. The primary outcome was acute severe ulcerative colitis (ASUC), and secondary outcomes were UC-related admission, medication treatment escalation, disease extension and surgery. Predictive performance was assessed using receiver operating characteristic (ROC) curves. RESULTS: Among 300 patients, 15.3% developed ASUC. Robust correlations were observed among the three scoring systems and were with elevated serum inflammatory markers. The DUBLIN score exhibited superior predictive ability for UC-related admission (AUC 0.751; 95%CI 0.698-0.799) and medication treatment escalation (AUC 0.735; 95% CI 0.681-0.784). No statistical differences were found among three scoring systems for predicting ASUC, disease extension, and surgery. Employing respective cut-offs of 2, 11.25, and 3, higher MES (HR = 3.859, 95% CI 1.636-9.107, p = 0.002), MMES (HR = 3.352, 95% CI 1.879-5.980, p < 0.001), and DUBLIN score (HR = 5.619, 95% CI 2.378-13.277, p < 0.001) were associated with an increased risk of developing ASUC. CONCLUSION: The DUBLIN score, assessing the overall inflammatory burden of the intestinal tract, outperforms the MMES in predicting admission and medication treatment escalation related to UC. Its integration into clinical practice has the potential to enhance risk stratification for patients with UC.

Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, Ulcerative Colitis: A Phase II Study.

BACKGROUND & AIMS: Current therapies for ulcerative colitis (UC) fail to achieve satisfactory disease control. Selective inhibition of Janus kinase (JAK) type 1 may improve clinical outcomes in patients with UC while avoiding the side effects associated with pan-JAK inhibition. The safety and efficacy of the selective JAK1 inhibitor ivarmacitinib (formerly SHR0302) were evaluated in patients with moderate-to-severe, active UC. METHODS: AMBER2 was a double-blind, placebo-controlled, phase II trial conducted at 63 clinical centers in China, the United States, and Europe. Patients (N = 164) were randomized 1:1:1:1 to receive oral ivarmacitinib 8 mg once daily (QD), 4 mg twice daily (BID), or 4 mg QD, or placebo for 8 weeks, followed by an 8-week extension period. The primary endpoint was clinical response rate at week 8. Hochberg's procedure was used to control the study-wise type 1 error at alpha=0.1. RESULTS: A total of 146 (89.0%) patients completed 8 weeks of treatment. Week 8 clinical response rates were significantly higher in the 8 mg QD (46.3%; P = .066), 4 mg BID (46.3%; P = .059), and 4 mg QD (43.9%; P = .095) groups vs placebo (26.8%). Week 8 rates of clinical remission were 22.0% (P = .020), 24.4% (P = .013), and 24.4% (P = .011) in the 3 ivarmacitinib treatment groups, respectively, vs 4.9% for placebo. During the initial 8-week period, treatment-emergent adverse events occurred in 43.9% to 48.8% of ivarmacitinib-treated patients and in 39.0% of the placebo group, and were predominantly mild. There were no deaths, or major adverse cardiovascular or thromboembolic events. CONCLUSION: Ivarmacitinib demonstrated clinical efficacy and was well tolerated in patients with moderate-to-severe, active, UC. Ivarmacitinib represents a promising new treatment for moderate-to-severe UC. CLINICALTRIALS: gov number, NCT03675477.

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis: A Randomized Clinical Trial.

Importance: Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. Objective: To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Design, Setting, and Participants: Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Interventions: Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. Main Outcomes and Measures: The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Results: Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Conclusions and Relevance: Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03235752.

Impact of COVID-19 outbreak on the care of patients with inflammatory bowel disease: A comparison before and after the outbreak in South China.

BACKGROUND AND AIMS: Epidemics pose a great challenge to health care of patients. However, the impact of unprecedented situation of COVID-19 outbreak on health care of inflammatory bowel disease (IBD) patients in real-world setting has seldom been investigated. METHODS: We performed an observational study in a tertiary referral IBD center in China. The mode of health care and medication use was compared before and after COVID-19 outbreak. Electronic questionnaire surveys were performed among gastroenterologists and IBD patients to investigate the impact of COVID-19 outbreak on their attitudes towards telemedicine. RESULTS: COVID-19 outbreak resulted in substantial decrease of patients participating in standard face-to-face visit during 1 month post-outbreak (n = 51) than pre-outbreak (n = 249), whereas the participation in telemedicine was significantly higher than comparable period in 2019 (414 vs 93). During the 1 month after COVID-19 outbreak, 39 (39/56, 69.6%) patients had their infliximab infusion postponed with the mean delay of 3 weeks. The immunomodulator use was similar between pre-outbreak and post-outbreak. Six elective surgeries were postponed for a median of 43 days. In post-outbreak period, 193 (193/297, 64.98%) of the surveyed physicians have used telemedicine with an increase of 18.9% compared with 46.13% (137/292) in the pre-outbreak period (P < 0.001); 331 (331/505, 65.54%) of the surveyed IBD patients supported that the use of telemedicine should be increased in future health care. CONCLUSION: COVID-19 outbreak resulted in a great change in health-care access among IBD patients including decrease in standard face-to-face visit and delay of biologics use. There was an increased use and need of telemedicine after COVID-19 outbreak.

DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. METHODS: DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. RESULTS: DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn's disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. CONCLUSIONS: During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.

Risk factors and long-term outcome of disease extent progression in Asian patients with ulcerative colitis: a retrospective cohort study.

BACKGROUND: The incidence of Ulcerative colitis (UC) in Asia is increasing but reports on its long-term course are few. The aim of this study was to identify risk factors predictive of extent progression in Asian patients with UC and to evaluate the clinical outcome by longitudinal follow-up. METHODS: We retrospectively analyzed 518 UC patients without ascending colon involvement at diagnosis who were regularly followed and underwent colonoscopy between 2003 and 2016 in an Asian tertiary referral center. Proximal disease extension and associated risk factors were analyzed. RESULTS: A total of 91 (17.6%) patients experienced proximal disease extension followed for a median period of 7.5 years. The median time for extent extension was 16.1 months (interquartile range (IQR) 8.3-42.2). The cumulative rate of disease extension was 9.9, 14.9, 19.6, 24.6 and 30.5% at 1,2,3,4 and 5 years after diagnosis. 43 (12.0%) patients with E1/E2 progressed to E3, and 40 (21.9%) with E1 progressed to E2. Of patients diagnosed with E3 involvement limited to the hepatic flexure distally, 8 (13.3%) progressed to pancolitis. Cox regression analysis found that disease extent at diagnosis was the sole predictor of disease extension (odds ratio (OR),1.74, 95% confidence interval (CI) 1.18-2.57, p = 0.01). Proximal disease extension was associated with disease relapse (p = 0.03) and increased use of steroids and immunosuppressive agents (p <  0.01). CONCLUSION: UC is a dynamic disease and that the disease extension in Asians was comparable to that in Caucasians. Proximal disease extension increased the risk of disease flare and treatment intensification.

Current diagnosis and management of Crohn's disease in China: results from a multicenter prospective disease registry.

BACKGROUND: This study aimed to understand the disease characteristics and treatment outcomes of Crohn's disease (CD) in a real-world setting in China. METHODS: In this prospective, non-interventional, multicenter disease registry, adults (≥18 years) with existing and newly diagnosed CD were recruited from 14 medical centers across China from January 2015 to January 2017. The study consisted of the enrollment and follow-up periods, of 12 months each. Demographic, clinical characteristics, diagnostic duration and management of CD at enrollment were evaluated. Logistic regression analysis and stepwise multivariate logistic regression analysis used to assess the relationship between the risk factors and CD. RESULTS: Of 504 enrolled patients, 499 (99.0%) were eligible for analysis. The mean (SD) age at study enrollment was 32.3 (11.43) years and the majority (69.7%) of participants were male. In the past 15 years, a sustained decrease of the period of time in the diagnosis of CD was observed, at about 39.4 (24.11) months in 2010, which decreased to 3.1 (2.13) months in 2015. The most common presenting symptoms of CD included abdominal pain (78.0%), diarrhea (58.1%), weight loss (52.9%) and fever (30.1%). Oral ulcer (19.4%) and arthritis (9.8%) were the most common extra-intestinal manifestations. Non-stricturing non-penetrating (B1) (49.9%) behavior and ileocolonic involvement (L3) (56.2%) location were more frequent. Perianal disease was observed in 29.1% of the patients. Around 23.8% (119/499) patients had CD-related surgery other than perianal disease surgery. Older age at enrollment, longer disease course, complicated disease behavior and absence of perianal disease were all surgery risk factors (p < 0.05). The most common medications was immunomodulators (e.g., azathioprine) (41.5%), anti-TNFα agents (32.9%) and aminosalicylates (20.6%). The mean (SD) Crohn's Disease Active Index (CDAI) score was 159.1 (91.45) and almost half of the patients (49.1%, 81/165) were in remission. CONCLUSIONS: This study demonstrated the CD-disease characteristics, risk factors of CD-related surgery and perianal disease, and treatment strategies in a real-world setting in China and may help in developing programs to diagnose and manage patients with CD.

Low 6-thioguanine nucleotide level: Effective in maintaining remission in Chinese patients with Crohn's disease.

BACKGROUND AND AIM: Measuring 6-thioguanine nucleotide (6-TGN) level is useful in optimizing dose of azathioprine (AZA) and monitoring for toxicity. Lower dose of AZA was suggested for maintenance of clinical remission in Asian patients than Caucasian patients with Crohn's disease (CD). However, the optimal 6-TGN threshold required in Asian patients is undetermined. Therefore, the aim of the current study is to explore the optimal 6-TGN threshold required in Asian patients with CD for maintenance of clinical remission. METHODS: A retrospective cohort study in a tertiary referral center recruited 252 CD patients. The primary endpoint was disease relapse. The levels of 6-TGN and AZA dose were compared in remission group and relapse group. Remission rate was compared across the increased 6-TGN level and dose range. RESULTS: Patients with 6-TGN range of 0-180.94 pmol/8 × 108 red blood cells (RBC) had lower remission rate compared with those with 180.94-255.50 pmol/8 × 108 RBC (P = 0.020). Quartile analysis showed that increasing 6-TGN level beyond 180 pmol/8 × 108 RBC produced negligible gain in rate of remission. Frequency of adverse events significantly increased in patients with 6-TGN level > 355 pmol/8 × 108 RBC (8.0% with 6-TGN > 355 pmol/8 × 108 RBC vs 2.7% with 6-TGN < 355 pmol/8 × 108 RBC, P = 0.035). CONCLUSION: Our study suggested that optimal 6-TGN threshold required to maintain clinical remission in Chinese patients was 180-355 pmol/8 × 108 RBC.

Prolonged azathioprine treatment reduces the need for surgery in early Crohn's disease.

BACKGROUND AND AIM: Whether an early use of azathioprine (AZA) can alter the natural history of Crohn's disease (CD) remains debated. The aim of this study is to evaluate the impact of AZA on disease progression in a cohort of patients with early CD. METHODS: This longitudinal cohort study examined patients with early CD defined as disease duration ≤ 18 months and no previous use of disease-modifying agents according to Paris definition. The primary outcome was the proportion of CD-related intestinal surgery. Cox regression analysis was performed to identify potential predictive factors of CD progression. RESULTS: One-hundred and ninety patients with early CD were enrolled in the study. After a median follow-up of 57 months (interquartile range, 31.3-76.2), 31 patients underwent abdominal surgeries, 48 patients were hospitalized, and 68 patients experienced clinical flares. The cumulative rate of remaining free of CD-related bowel surgery, hospitalization, and flare at 5 years on AZA treatment was 0.65, 0.59, and 0.39, respectively. Three independent predictors of CD-related operations were identified: prior bowel resection (hazard ratio [HR], 9.23; 95% confidence interval [CI] 3.67-23.23), smoker (HR, 4.0; 95% CI 1.38-11.65), and hemoglobin < 110 g/L at the time of initiation of AZA (HR, 4.36; 95% CI 1.80-10.58). Conversely, AZA treatment duration > 36 months (HR, 0.04; 95% CI 0.01-0.15) was associated with reduced CD-related operations. CONCLUSION: Prior bowel resection, smoking, and hemoglobin < 110 g/L at the time of initiation of AZA were risk factors associated with intestinal surgery in patients with early CD. However, prolonged use (≥ 36 months) of AZA was associated with a more favorable disease course of early CD.

Thiopurines prevented surgical recurrence in patients with Crohn's disease after intestinal resection: Strategy based on risk stratification.

BACKGROUND AND AIM: Thiopurines (TPs) are effective in reducing clinical and endoscopic recurrence in postoperative patients with Crohn's disease (CD). However, whether TPs could prevent surgical recurrence (SR) remains unknown. We aimed to explore whether TPs could prevent SR and identify risk factors associated with SR. METHODS: This was a retrospective cohort study of 246 postoperative patients with CD. Cox proportional hazard model was used to identify risk factors for SR. Patients were stratified according to the presence of risk factors. RESULTS: A total of 50 (20.3%) patients suffered SR after a mean follow up of 54.3±46.4 months. Multivariable analysis showed independent risk factors for SR were penetrating disease behavior (HR 8.628; 95% CI 1.573-47.341; P = 0.01), ileocolonic disease location (HR 2.597; 95% CI 1.047-6.445; P = 0.04) and isolated upper gastrointestinal disease (UGID) location (HR 5.082; 95% CI 1.496-17.267; P = 0.009). However, use of TPs after surgery significantly reduced the risk of SR (HR 0.120; 95% CI 0.063-0.231; P < 0.001). When stratifying patients according to risk factors, there was no statistical difference of SR between patients treated or not by TPs (P = 0.08) in low-risk group (n = 46). However, in high risk group (n = 200), patients with TPs use had a lower risk of SR than those without TPs (HR 0.093; 95% CI 0.048-0.178; P < 0.001). CONCLUSIONS: Penetrating disease behavior and ileocolonic/isolated (UGID) location were associated with SR in CD patients. TPs use was beneficial in decreasing risk for SR in CD patients at high risk.

A New Model Based on 25-Hydroxyvitamin D3 for Predicting Active Crohn's Disease in Chinese Patients.

BACKGROUND: The association between vitamin D3 and activity of Crohn's disease (CD) is unclear in Chinese patients. In this study, we aimed to evaluate the correlations between serum levels of 25-hydroxyvitamin D3 (25(OH)D3) and disease activity and predict active disease based on vitamin D status. METHODS: Between January 2014 and December 2017, 346 CD patients from the First Affiliated Hospital of Sun Yat-sen University were recruited and categorized into a group with 25(OH)D3 ≤ 20 ng/ml and a group with 25(OH)D3 > 20 ng/ml. The clinical characteristics, medication, and health-care needs were compared between the groups. The correlations among 25(OH)D3 and routine serum biomarkers and disease activity were examined. The predictive efficiency of 25(OH)D3 and other biomarkers for active diseases was also explored using receiver-operating characteristic (ROC) curve analysis. A new predictive model, -(5∗25(OH)D3 + 2∗Hb) + ESR, and a nomogram were established using Logistic Regression. RESULTS: Patients with 25(OH)D3 ≤ 20 ng/ml had higher serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and platelets (PLT) and lower levels of hemoglobin (Hb) and albumin (ALB). Serum levels of 25(OH)D3 were inversely correlated with the score of Crohn's Disease Activity Index (CDAI) (r s = -0.608). ROC analysis showed a better predictive value of -25(OH)D3 and the new model with areas under curve (AUC) of 0.804 and 0.879, respectively, than those of CRP (0.693) and ESR (0.713) in disease activity. A nomogram for prediction was established with a c-index of 0.882. CONCLUSIONS: Serum levels of 25(OH)D3 negatively correlated with CD activity in Chinese patients. The new model and a nomogram based on 25(OH)D3 showed a better efficiency in predicting disease activity in CD patients but warrants further study.

Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis.

BACKGROUND & AIMS: It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. METHODS: We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. RESULTS: We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P < .001). However, the pooled analysis did not demonstrate a significant difference in trough levels of anti-TNF agents between patients with versus without concurrent use of immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I2 = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). CONCLUSIONS: In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease.

Feasibility of endoscopic submucosal dissection for upper gastrointestinal submucosal tumors treatment and value of endoscopic ultrasonography in pre-operation assess and post-operation follow-up: a prospective study of 224 cases in a single medical center.

BACKGROUND AND AIMS: Diagram, diagnosis, and treatment with endoscopic submucosal dissection (ESD) for upper gastrointestinal submucosal tumors (SMTs) remain controversial, although endoscopic ultrasonography (EUS) and ESD have been established in diagnosis and treatment of SMTs in decades, respectively. In this study, we have investigated prospectively the profile of upper gastrointestinal SMTs, assessed the effect and feasibility of ESD in upper gastrointestinal SMTs treatment, as well as value of EUS in pre-ESD diagnosis and post-ESD follow-up for gastrointestinal SMTs. METHODS: The upper gastrointestinal SMTs patients detected with endoscopy were further checked by EUS, then received series ESD treatment, and fulfilled 3- and 12-month follow-up EUS detection between July 2011 and March 2015. The parameters of SMTs with EUS examination (size, original layer) and treatment with ESD (en bloc resection rate, procedure time, procedure-related complications) were investigated and analyzed. RESULTS: A total number of 224 patients with upper gastrointestinal SMTs were enrolled, and 108 (48.2 %) were men. The mean age was 50.4 ± 12.0 years (range 19-77 years). In total, 92 (41.1 %), 14 (6.3 %), 61 (27.2 %), 22 (9.8 %), 25 (11.2 %), and 10 (4.5 %) SMTs were located in esophagus, cardiac, fundus, body and antrum of stomach, duodenum, respectively. Two hundred and eight (92.9 %) patients were successfully treated with an en bloc ESD, while other 16 patients (7.1 %) suffered ESD failure (5.3 %, 12 case) or severe complications (1.8 %, 4 cases). The mean procedure time of ESD was 47.4 ± 27.3 min (range 10-180 min). The mean size of the SMTs measured with ESD samples was 13.6 ± 9.5 mm (range 4-113 mm). In total, 87 (38.8 %), 23 (10.3 %), and 114 (50.9 %) tumors originated from muscularis mucosa, submucosa, and muscularis propria, respectively. The majority of SMTs were leiomyoma (109, 48.7 %) and gastrointestinal stromal tumors (GIST) (77, 34.4 %), while other SMTs were confirmed as ectopic pancreas (21, 9.4 %), adenoid tumor (8, 3.6 %), lipoma (5, 2.2 %), neuroendocrine tumor (3, 1.3 %), and granulosa cell tumor (1, 0.4 %). The accuracy rate of EUS in pathological diagnosis or original layer was 82.6 % (185/224) or 74.6 % (167/224). Residual tumors were detected with EUS in 3 patients (1.3 %) in 3-month follow-up and no recurrence during 12-month follow-up period. CONCLUSIONS: The predominant SMTs in upper gastrointestinal tract were leiomyoma in esophageal tumors which originated from muscularis mucosae and GIST in stomach which originated from muscularis propria detected satisfactorily with EUS. This study showed that ESD was a safe and effective treatment for upper gastrointestinal SMTs.

[Clinical manifestations of Crohn's disease misdiagnosed as appendicitis].

OBJECTIVE: To analyze the clinical manifestations and identify independent diagnostic predictive factors for Crohn's disease (CD) initially diagnosed as appenicitis and treated by surgery. METHODS: The medical records of patients diagnosed as acute appendicitis upon admission and treated by surgical operation in the First Affiliated Hospital of Sun Yat-sen University from January 2000 to December 2014 were retrospectively analyzed. Based on postoperative pathological examination and clinical examination results, 28 CD patients were identified (CD group), and for each CD case, 3 controls with confirmed diagnosis of appendicitis were included (appendicitis group, n=84). Clinical manifestations and laboratory examination results of the two groups were analyzed with multivariable Logistic regression to determine independent diagnostic predictive factors for CD initially misdiagnosed as appendicitis. RESULTS: Altogether 112 patients were enrolled, with a male-to-female ratio of 1.04:1 (57:55), and a median age of 36 years. No significant differences were found in gender, age, and body temperature between the CD group and appendicitis group (all P>0.05). In the appendicitis and CD groups, median duration (Q1-Q3) of abdominal pain was 24 (14-48) hours vs 216 (96-384) hours, proportion of patients with lower right abdominal pain was 98.8% (83/84) vs 75.0% (21/28), proportion of patients with shifting lower right abdominal pain was 98.8% (83/84) vs 7.1% (2/28), proportion of patients with local lower right peritonitis was 95.2% (80/84) vs 53.6% (15/28), proportion of patients with change of bowel emptying habit or stool consistency was 7.1% (6/84) vs 46.4% (13/28), proportion of patients with history of chronic abdominal pain or diarrhea was 10.7% (9/84) vs 75.0% (21/28), preoperative white blood cell count was (14.08±4.13)×10(9)/L vs (8.00±3.42)×10(9)/L, preoperative neutrophil count was (11.34±4.10)×10(9)/L vs (5.58±3.22)×10(9)/L, preoperative hemoglobin was (139.52±19.90) g/L vs (107.65±21.68) g/L, preoperative red blood cell count was (4.85±0.74)×10(12)/L vs (4.28±0.87)×10(12)/L, and preoperative platelet count was (220.68±74.47)×10(9)/L vs (302.09±71.65)×10(9)/L, all with significant differences (all P<0.05). Multivariable analysis showed that change of bowel emptying habit and stool consistency (OR=36.712, 95%CI: 1.672-806.103, P=0.022), medical history of chronic abdominal pain or diarrhea (OR=60.142, 95%CI: 4.501-803.573, P=0.002), lower preoperative hemoglobin level (OR=0.909, 95%CI: 0.858-0.963, P=0.001), and higher platelet count (OR=1.027, 95%CI: 1.007-1.047, P=0.008) were independent predictive factors for CD. CONCLUSIONS: CD should be considered in cases initially diagnosed as appendicitis with change of bowel emptying habit and stool consistency, medical history of chronic abdominal pain or diarrhea, anemia, and increased platelet count.

Factors associated with progression to surgery in Crohn's disease patients with endoscopic stricture.

BACKGROUND AND STUDY AIMS: Early intensive therapy should be considered for Crohn's disease patients at high risk of surgery. Factors associated with the development of intestinal strictures or obstructions in Crohn's disease were explored. The aim of our study was to identify risk factors predictive of subsequent surgery in patients with endoscopically identified stricture. PATIENTS AND METHODS: In this case-control study, 86 patients with established Crohn's disease and endoscopic strictures between 2003 and 2012 were divided into two homogeneous arms: surgery group and control group. The primary outcome was surgery. Cox regression analysis was used to evaluate risk factors associated with subsequent surgery. RESULTS: 33 of 86 patients (38.4 %) underwent stricture-related surgery during follow-up. The cumulative rates for surgery were 15.1 %, 19.8 %, 23.3 %, 30.2 %, and 38.4 % at 1, 3, 6, 12, and 36 months, respectively. Independent risk factors associated with subsequent surgery in Crohn's disease patients with endoscopic strictures were: smoking (hazard ratio [HR] 5.49, 95 % confidence interval [95 %CI] 2.32 - 13.02; P = 0.000); disease duration at first detection of stricture less than 3 years (HR 3.89, 95 %CI 1.6 - 9.5; P = 0.003); presence of obstructed bowel symptoms (HR 2.68, 95 %CI, 1.24 - 5.78; P = 0.012) and Crohn's Disease Activity Index (CDAI) > 220 (HR 2.68, 95 %CI 1.22 - 5.90; P = 0.015). For patients with 3 and 4 risk factors, the positive predictive values for subsequent surgery were 0.73 and 1.00, respectively. CONCLUSION: For Crohn's disease patients with endoscopic stricture, factors predictive of subsequent surgery were smoking, disease duration at first detection of stricture less than 3 years, presence of obstructed bowel symptoms, and CDAI > 220.

Imbalances of CD4(+) T-cell subgroups in Crohn's disease and their relationship with disease activity and prognosis.

BACKGROUND AND AIM: The CD4(+) T-cell subgroups play central pathophysiological roles in Crohn's disease (CD); however, their clinical relevance requires additional clarification and remains controversial. We investigated their balance in Chinese CD patients and explored their clinical significance. METHODS: Peripheral blood mononuclear cells and serum were collected from 46 Chinese CD patients and 23 healthy donors. Circulating Treg, Th1, Th2, and Th17 cells were flow cytometrically analyzed. Subgroup-restricted transcription factor expression was determined by real-time polymerase chain reaction. Serum concentrations of the main cytokines produced by each subgroup were measured by cytometric bead arrays or enzyme-linked immunosorbent assay. RESULTS: Lower Treg proportion (6.0 ± 1.2% vs 7.8 ± 1.5%, P = 0.030), FOXP3 mRNA expression (0.58-fold, P = 0.030), and circulating soluble TGFß-1 (19.1 ± 9.9 vs 32.7 ± 16.8 ng/mL, P = 0.038) were observed in CD patients versus controls. The Th1 and Th17 proportions were higher in CD patients (17.8 ± 6.6% vs 7.8 ± 1.5%, P < 0.001; and 3.7 ± 1.8% vs 1.8 ± 0.7%, P = 0.022, respectively), as were transcription factors T-bet (4.6-fold, P = 0.043) and RORγt (14-fold, P < 0.001) and related cytokines (P < 0.05). Th2 proportion, GATA3 mRNA expression, and serum interleukin-4 concentration in CD patients were similar to controls (P > 0.05). Treg/Th1 and Treg/Th17 ratios were higher in inactive versus active CD patients (0.6 ± 0.4 vs 0.3 ± 0.1, P = 0.022; and 3.7 ± 2.0 vs 1.7 ± 1.4, P = 0.013, respectively). During follow-up, patients with lower Treg/Th1 and Treg/Th17 ratios were at higher recurrence risk. CONCLUSIONS: Imbalances among Treg, Th1, and Th17 subgroups were found in Chinese CD patients. Treg/Th1 and Treg/Th17 ratios are associated with disease activity and are potential prognostic indicators for predicting CD recurrence.

[The efficacy and safety of methotrexate in refractory Crohn's disease].

OBJECTIVE: To assess the efficacy and safety of methotrexate(MTX) on refractory Crohn's disease(CD). METHODS: A total of 35 consecutive refractory CD patients in the First Affiliated Hospital of Sun Yat-Sen University treated with MTX were retrospectively analyzed. Clinical data from June 2004 to December 2012 were collected from the database of inflammatory bowel disease (IBD) center. Clinical responses and drug side effects were recorded and analyzed. RESULTS: Thirty-five refractory CD patients were identified including 23 cases intolerant to azathioprine (AZA)/6-mercaptopurine(6-MP), six cases ineffective to AZA/6-MP, 19 cases dependent on steroid. After treatment of MTX for 12 weeks [15(5-20) mg/week], a clinical response was obtained in 80% patients (28/35), including 51.4% (18/35) in remission and 28.6% (10/35) in improvement. The median Crohn's disease activity index (CDAI) scores at the onset and 12 weeks after MTX therapy were 99.2 (75.8, 174.7) and 61.5 (36.0, 106.6) respectively. The median single dose and duration of MTX were 15 (5-20) mg/week and 6.0(0.5-53.0) months respectively. The median cumulative dose was 480 (20-2615) mg. Among the 26 patients dependent on steroid, 21 achieved discontinuation of steroid with a median time of 10 (6-20) weeks after treatment of MTX. Side effects were recorded in 12 patients (34.3%), but usually mild and improved after drug with drawal. CONCLUSIONS: MTX is an effective and steroid-sparing agent for refractory CD. Side effects of MTX are mild and tolerable.

[Clinical characteristics and risk factors of refractory Crohn's disease].

OBJECTIVE: To analyze the clinical characteristics and risk factors of refractory Crohn's disease (CD). METHODS: All clinical data of confirmed consecutive CD patients were collected from our hospital between January 2003 and June 2013. The patients' demographic data, clinical features, therapeutic regimens and laboratory examinations were analyzed. A multivariate Logistic regression was performed to identify the risk factors of refractory CD. RESULTS: (1) A total of 402 confirmed CD patients were recruited for analysis. The prevalence of refractory CD was 33.8% (136/402). The rates of steroid-dependency was 37.0% (97/262) in 262 patients with a history of steroid use and the rate of thiopurines ineffectiveness was 26.9% (79/294) in 294 patients with a history of thiopurines-use; (2) Univariate analysis showed that disease location (L3 type), abdominal pain, diarrhea, fever, abdominal tenderness, perianal lesion, steroid use, AZA/6-MP use, leucocyte, hemoglobin (Hb), platelet level and high-sensitivity C-reactive protein (HsCRP) were significantly different between refractory and non-refractory CD patients (all P < 0.05) . Multivariate Logistic regression showed that steroid use (OR = 6.516, 95% CI: 2.884-14.722, P = 0.000) and low Hb (OR = 1.023, 95% CI: 1.008-1.037, P = 0.002) were independent risk factors related to refractory CD; (3) Univariate analysis showed that Hb level, erythrocyte sedimentation rate (ESR) were significantly different between steroid-dependent and non-steroid-dependent groups (all P < 0.05) . Multivariate Logistic regression showed that only low Hb level (OR = 1.021, 95% CI: 1.006-1.036, P = 0.005) was an independent risk factor related to steroid-dependency; (4) Univariate analysis showed that disease location (L3 type), perianal lesion, abdominal pain, diarrhea, fever, abdominal tenderness, platelet level, steroid use, steroid-dependency were significantly different between thiopurines-ineffective and thiopurines-effective groups (all P < 0.05) . Multivariate Logistic regression showed that perianal lesion (OR = 2.085, 95% CI: 1.007-4.039, P = 0.029), abdominal tenderness (OR = 2.943, 95% CI: 1.452-5.964, P = 0.003) and steroid-dependency (OR = 3.599, 95% CI: 1.847-7.013, P = 0.000) were independent risk factors related to thiopurines-ineffectiveness. CONCLUSIONS: Nearly one third CD patients became refractory during the course of disease. Low Hb and steroid use are independent risk factors. Low Hb is an independent risk factor related to steroid-dependency. Perianal disease, abdominal tenderness and steroid-dependency are independent risk factors related to thiopurines- ineffectiveness.

Lymphocyte subsets for predicting inflammatory bowel disease progression and treatment response: a systematic review.

Background: Lymphocytes play a key role in the pathogenesis of inflammatory bowel disease (IBD) and are widely explored as promising prognostic indicators. We aimed to outline the existing evidences on the capability of lymphocyte subpopulations to predict disease progression and treatment response in patients with IBD. Methods: The protocol for this review was registered in PROSPERO (registration ID: CRD 42022364126). Systematic retrieval was conducted using PubMed, Embase, and Web of Science databases. Original articles on the prognostic value of lymphocyte subsets in IBD published up to April 8, 2023 were eligible for inclusion. The Newcastle-Ottawa Scale was used to evaluate the risk of bias. Results: Twenty studies were ultimately included: eight evaluated the prediction of disease progression and 12 focused on the prediction of treatment response. According to the Newcastle-Ottawa Scale, three studies were of high quality, 16 were of moderate quality, and only one was of low quality. T-cell subpopulations, including CD4+ T cells, CD8+ T cells, and γδ T cells, are revealed to have prognostic capacity. Transmembrane tumor necrosis factor α-bearing lymphocytes, CD4+ T cells, CD8+ T cells, and Plasma cells are found to have the potential to predict the response to anti-TNFα agents. In contrast memory T cells, CD4+ T cells, and naïve B cells may predict the response to vedolizumab. Conclusions: This systematic review identified several potential lymphocyte subset-related predictors. If verified in large cohort prospective studies, these findings could aid clinical decision-making. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022364126.

Predicting Factors of Long-term Outcome of Gastrointestinal Behçet's Disease: A Chinese Retrospective Study.

PURPOSE: Behçet's disease (BD) is a complex disorder affecting multiple systems and organs, and gastrointestinal BD is poorly understood. We aimed to identify factors influencing the long-term outcomes of patients with gastrointestinal BD. METHODS: Consecutive patients with gastrointestinal BD were analyzed retrospectively. Data on the following clinical characteristics were collected: sex, age at diagnosis, symptoms, endoscopic findings, medical treatments, and surgery. Mucosal healing and surgical rates at 1, 2, and 5 years were evaluated. Log-rank test and Cox proportional hazards regression models were used to evaluate the factors affecting long-term outcomes. FINDINGS: Baseline data of 175 patients with gastrointestinal BD were included. The mean (SD) age at diagnosis was 38.3 (12.9) years. The typical clinical symptoms were oral ulcer (72.6%), abdominal pain (71.4%), and weight loss (41.1%). The most commonly involved location was the ileocecum; isolated oval ulcer was the most common ulcer type. Seventeen patients (9.7%) underwent 18 surgeries after inclusion. The cumulative surgical rates were 8.6% (n/N = 15/175), 8.6% (n/N = 15/175), and 9.1% (n/N = 16/175) in 1, 2, and 5 years, respectively. Data from 101 patients who underwent at least 2 endoscopies were included in the analysis for mucosal healing. Kaplan-Meier curve showed that the cumulative mucosal healing rates at 1, 2, and 5 years were 34.7% (n/N = 35/101), 41.6% (n/N = 42/101), and 61.4% (n/N = 62/101), respectively. We compared cumulative mucosal healing rates between 4 treatment groups, including 5-aminosalicylic acid (3% [n/N = 3/101]), mono-immunosuppressant (31.7% [n/N = 32/101]), combined therapy (36.6% [n/N = 37/101]), and escalation therapy (28.7% [n/N = 29/101]), and found that mono-immunosuppressant achieved earlier mucosal healing than combined therapy (P = 0.0008) and escalation therapy (P = 0.0008). The univariate analysis showed that moderate to severe disease activity (P = 0.013, P = 0.004), diameter of the maximal ulcer >4 cm (P = 0.002), and nonsimple esophageal involvement (P < 0.001) were risk factors, and number of ulcers between 2 and 5 was the protective factor of mucosal healing (P = 0.001). Multivariate regression analysis indicated that nonsimple esophageal involvement (P < 0.001) and the maximal ulcer >4 cm (P = 0.041) were independent risk factors of mucosal healing. IMPLICATIONS: Most patients with gastrointestinal BD need long-term treatment to achieve mucosal healing. The location and size of ulcers have a significant impact on the mucosal healing of gastrointestinal BD.